For the purpose of extending the duration of active ingredients and reducing side effects, a percutaneous administration route which makes it feasible to strictly control doses has recently been studied as a substitution for oral administration or injection. For example, percutaneous preparations including topical preparations of antiinflammatory agents and systemic preparations of nitroglycerin, isosorbide dinitrate, scopolamine, estradiol or the like have been developed.
Also with respect to clonidine acting as a hypotensive, a percutaneous preparation of clonidine which maintains a constant level in blood over 7 days or more thus achieving a prolonged duration has been proposed in place of oral tablets containing clonidine hydrochloride as described in MacGregor, T. R., et al., Clin. Pharmacol. Ther., Vol. 38(3), p. 278 (1985), U.S. Pat. No. 4,201,211, and JP-A-54-20129 (the term "JP-A" as used herein means an "unexamined published Japanese patent application"].
A dose of clonidine, given orally, usually lasts for about 8 hours and therefore should be administered three times a day. This is a trouble to a patient, often causing the patient to forget to take the medicine, which may lead to serious symptoms due to a break in the effect. For this reason, attention has been called to percutaneous preparations of clonidine. Conventional percutaneous preparations of clonidine comprise a support sheet substantially impermeable to clonidine having thereon a clonidine-containing layer, a layer controlling release of clonidine, and an adhesive layer for fixing to the skin in this order.
U.S. Pat. No. 4,765,974 and JP-B-63-20806 (the term "JP-B" as used herein means an "examined published Japanese patent application") disclose percutaneous preparations comprising a support of various kinds having thereon an active ingredient-containing layer comprising a specific acrylate copolymer having dispersed therein clonidine and/or clonidine hydrochloride as an active ingredient with citric acid and/or succinic acid as a decomposition inhibitor.
JP-B-63-21647 discloses a percutaneous preparation of clonidine comprising a porous fluorine-containing resin film or sheet having a specific moisture permeability having thereon an active ingredient-containing layer.
While these conventional preparations for percutaneous administration of clonidine produce considerable effects in percutaneous absorption of clonidine, sustained clonidine release, and prevention of decomposition of clonidine during preservation (stability), no attention has been directed to suitability of the support. In particular, a support having no substantial air permeability would be of great irritation to the skin, giving rise to an extremely serious problem in practical application. JP-B-63-21647 supra suggests to use a porous fluorine-containing resin film, etc. having specific permeability to moisture as a support of low skin irritation, but sufficient study is not given to the optimum combination of components constituting the layer containing clonidine and also serving for fixing to the skin. In particular, having a hypotensive effect, clonidine must be administered under strict dose control and, therefore, adhesion to the skin is one of important subjects to consider. That is, should the preparation be partly peeled apart from the skin due to poor adhesion, migration of clonidine through the skin is reduced, failing to obtain sufficient hypotensive effect as expected.
Accordingly, in developing percutaneous preparations of an active ingredient requiring strict dose control (control on the amount percutaneously absorbed), such as clonidine, the following requirements should be satisfied. (1) The preparations must have sufficiently satisfactory adhesion to the skin. For example, peeling of even 10% of the area adhered is unacceptable. (2) The active ingredient should be stably present in the preparations, prevented from decomposition during long-term preservation. (3) In order to achieve sustained release of the active ingredient for a prolonged period of time, irritation to the skin should be minimized. For example, the skin irritation index (hereinafter defined) should not exceed 30. (4) Because clonidine is relatively expensive, it is desired to increase availability of the active ingredient. In greater detail, the rate of release to the skin surface should be at least 15%.
Under the present situation, percutaneous preparations of clonidine satisfying the above-described requirements have not yet been developed.